Chemokines are a kind of cytokines which guide the directed migration of lymphocytes, and play an important role in inflammatory reaction, white blood cells extravasation, tissue infiltration, tumorigenesis and embryonic development. Chemokines, having a molecular weight of 8˜14 kDa, belong to the large family of the secreted signalling molecules, which currently comprises about 45 members with a common characteristic of having four cysteine (Cys) residues of which the positions are conserved. According to whether there are other amino acids between the two Cys residues near the N-terminal, the family is divided into four groups: CC, CXC, CXQC and C, wherein CC (also named as β-chemokines) and CXC (also named as α-chemokines) are the most two important groups.
The function of chemokines is mediated by chemokine receptors. At present, chemokine receptors are normally named in accordance with the character of the chemokines to which they specifically bind (for example, the chemokine receptors will be named as CCR if their ligands are the members of the CC chemokine subfamily). Chemokine receptors, which belong to the seven-transmembrane G-Protein-Coupled Receptor, contain seven conserved transmembrane domains formed by α-helical structure, with an extra cellular N-terminal and an intra cellular C-terminal domain. When combining with an agonist, chemokine receptors can couple to G-protein such that the extracellular signal can be transferred into cell. With the action of an agonist, chemokine receptors could trigger a series of intracellular signals and change cell behaviour, such as inhibiting the activity of adenylate cyclase (AC), triggering a flux in intracellular calcium, activating a series of protein kinase, guiding the directed migration of cells (chemotaxis) and affecting the release of cytokines.
There have currently been found 19 chemokine receptors, which are CCR1-11, CXCR1-6, XCR1 and CX3CR1. Chemokine receptors are thought to be an important mediator of inflammatory reaction and autoimmune diseases (Gerard et al., Nat Immunol, 2, 108-15 (2001)). Therefore, the regulator of chemokine receptors (including agonist and antagonist) can be used in many kinds of disease, such as inflammatory or allergic diseases, allergic reaction, autoimmune diseases, inflammatory bowel diseases, scleroderma, eosinophilic myositis, tumorigenesis and metastasis.
As a member of the chemokine receptor family, CCR5, whose endogenous agonists are RANTES, MIP-1α and MIP-1β, expresses in dendritic cells, T Lymphocytes, monocytes and macrophages derived from peripheral blood cells, and immune cells and inflammatory cells participating in maintenance of a long-term inflammatory reaction. Therefore, CCR5 may regulate the recruitment of T cells to the injured sites of inflammatory response so as to provide a new target for the treatment of inflammatory reaction and autoimmune diseases. For example, CCR5-deficient mice were protected from DSS-induced serious inflammations and mucosal ulcerations (Andres et al., J. Immunol., 164, 6303-12 (2000)); and a small molecule antagonist TAK-779 of CCR5 inhibited collagen-induced arthritis in mice (Yang et al., Eur J. Immunol., 32, 2124-32 (2002)). Hence, the antagonist of CCR5 can be used in the treatment of the diseases including asthma and local disorders (such as locality dermatitis and local anaphylaxis), rheumatoid arthritis, arteriosclerosis, psoriasis, sarcoidosis and other fibrotic diseases, autoimmune diseases (such as multiple sclerosis and inflammatory bowel disease). Further, because CD8+ T cells are related with chronic obstructive pulmonary diseases (COPD), CCR5's antagonist could be used to treat COPD also.
Besides the action in inflammation and immune reactions, chemokine receptors may also be the critical receptors during the cell invasion by parasites and viruses. For instance, Duffy receptor is the receptor for plasmodium entrying into erythrocytes, and people lacking of Duffy receptor are not easy to suffer from malaria. More importantly, several chemokine receptors participating in the invasion of HIV, are called HIV co-receptor.
It has showed that CD4 molecules on Th cells are essential for HIV invasion, but CD4 alone is not sufficient to mediate the fusion of HIV and cell. Further researches indicated that the other molecules named co-receptors of HIV invasion are CCR5, CXCR4, CCR2b, CCR3, CCR8 in chemokine receptors and, V28, STRL-33, GPR1, GPR15 and APJ in orphan receptors (Domes et al., Virology, 235, 179-90, (1997)). CCR5 and CXCR4 are the main co-receptors in vivo for HIV invasion, and CCR3 may involve in part of the HIV entry. CCR5 is the co-receptor of macrophage tropic (M-tropic) HIV-1, and CXCR4 is the co-receptor of T cell tropic (T-tropic) HIV-1. Therefore, CCR5 plays a key role in HIV spreading, and a substance regulating CCR5 can affect the spreading of M-tropic HIV-1 in people, and thus control the disease at an early stage. It has been found through in vitro experiments that chemokines which can bind to CCR5, including RANTES, MIP-1α and MIP-1β, could inhibit HIV infection by suppressing the invasion of M-tropic HIV-1 into cells. Some small molecular compounds that can bind to CCR5 and antagonize the function of CCR5 are also able to effectively inhibit the invasion of HIV into cells in vitro.
In summary, there is an urgent need in the art for developing compounds having a potential pharmaceutical application as a CCR5 antagonist.